The interest in the development of extended release preparations, in particular of those on the basis of biodegradable polymers, has increased significantly in the last years. Drug products based on these compositions can maintain therapeutically effective drug levels for weeks or months with drugs having a low oral bioavailability or a high first pass effect. This is especially applicable for the new generation of highly potent, biotechnologically derived drugs such as peptides and proteins. Daily injections are avoided because of the longer dosing intervals and, therefore, the patient compliance is improved.
In order to retard the release of the active compound, the active compound is embedded in a biodegradable polymer matrix or is surrounded with a polymer shell. The synthetic poly(lactide-co-glycolide) (PLGA) derivatives are predominantly used among water-insoluble polymers for this purpose because of their approval in marketed drug products. The biodegradable polymers are frequently used in drug products in the form of implants or microparticles.
Implants (commercial products: Profact Depot, drug: busereline acetate, Höchst Marion Roussel; Zoladex, drug: gosereline acetate, Zeneca) are mostly cylindrically shaped polymer rods with embedded active compound, which are prepared by melt extrusion or -compression. The disadvantages of these methods are high process temperatures, which can cause degradation of the active compound and problems of homogeneity with low dose active compounds. In addition, the required surgical procedures for implantation or the injection through large needles is not popular with patients.
Biodegradable microparticles (commercial products: Enantone Depot, drug: leuprolide acetate, Takeda Chemicals; Decapeptyl Depot, drug: triptoreline acetate, Ferring) can be injected easier in the form of aqueous dispersions of the microparticles and are therefore preferred by the patients when compared to implants. These microparticles are prepared by various methods, such as the solvent evaporation- or solvent extraction methods (e.g. EP 0 190 833), organic phase separation- (EP 0 052 510) or spray drying methods (EP 0 505 966).
In the solvent evaporation method, which is frequently used for the preparation of biodegradable microparticles, a drug is dissolved or dispersed in a solution of a biodegradable polymer (e.g., PLGA in methylene chloride). This drug-containing polymer phase is then emulsified in an external aqueous phase and forms drug-containing polymer droplets. The microparticles are obtained after evaporation of the solvent or after diffusion of the solvent in the external phase through the solidification of the polymer and are then separated from the aqueous phase (e.g., by filtration) and dried.
In the organic phase separation method, the coacervation into particles is induced by the addition of a nonsolvent (e.g., silicone oil) to a dispersion of the active compound in an organic polymer solution. The microparticles are hardened, filtered, washed and dried.
In the spray drying method, the microparticles are obtained by the spraying/drying of the active compound-containing organic polymer solution into a heated air stream and by the separation in a cyclone.
Commercially available biodegradable microparticle products therefore consist of a dry powder of the microparticles and an aqueous suspension vehicle, which is stored separately. The microparticles in dry form and the aqueous suspension vehicle are stored separately, for example in two-chamber syringes or in two ampoules, because of the hydrolytic instability of the biodegradable polymers. The biodegradable polymer would, during storage, hydrolytically degrade in direct contact with the aqueous suspension vehicle. The solid microparticles are then suspended in the aqueous suspension vehicle just prior to the administration and are then injected primarily subcutaneously or intramuscularly.
The described microencapsulation methods and the resulting microparticles can have various problems: (1) the use of toxic organic solvents and the solvent residuals in the product; (2) a large number of process- and formulation variables, which influence the properties of the microparticles and which have to be validated; (3) a low encapsulation efficiency and product yield; (4) the necessity of costly measures for the aseptic preparation or the risk of changes in the particle properties after irradiation of the final product; (5) stability problems during storage of the particles, for example changes in the release profile because of aging processes. In most instances, the microparticles are stored separately from the aqueous suspension vehicle in ampoules or two chamber syringes. This storage form requires a reconstitution step just prior to administration. The suspension of the microparticles and the subsequent injection can also cause difficulties due to agglomeration of the particles, residual microparticles in the syringe, clogging of the needle, etc.
WO 98/55100 describes compositions, which avoid some of the problems seen during the preparation and administration of microparticles and implants. These compositions form particles and/or implants after placement in the body of a human or an animal. The compositions comprise an inner, polymer-containing carrier phase and an external phase, which is immiscible or partially immiscible with the carrier phase, wherein the viscosity of the carrier phase is changed after a change in ambient conditions (e.g., placement in subject) such that a solidification of the polymer into particles or implants occurs.
According to WO 98/55100, an active compound-containing dispersion, consisting of an inner drug-containing carrier phase and a second external phase (e.g., an oil) may be prepared and be placed into the body. The inner carrier phase comprises a solution of a polymer (e.g., PLGA) and a solvent. The inner phase solidifies after placement in the body, for example through solvent diffusion in the body fluids or diffusion of body fluids into the carrier phase. For example, in the case of biodegradable polymers, the dispersion may be injected i.m. or s.c. The inner phase solidifies in contact with body fluids and forms particles.
A need exists for extended release preparations, which do not have the disadvantages inherent in the known art, for example the very tedious large-scale production of microparticles. In particular, there is a need for compositions of extended release particles, which are prepared just prior to administration from preproducts.